Bexxar: Low Risk of Secondary MDS/AML

Bexxar: Low Risk of Secondary MDS/AML

SAN DIEGOThere have been no reported cases of
treatment-related myelodysplastic syndrome and acute myeloblastic leukemia (tMDS/tAML)
in patients with low-grade non-Hodgkin’s lymphoma (NHL) treated initially with
the Bexxar therapeutic regimen (tositumomab and iodine-131 tositumomab).

John M. Bennett, MD, Professor of Medicine, Laboratory
Medicine and Pathology, Emeritus, at the University of Rochester Medical
Center’s James P. Wilmot Cancer Center, presented the study at the 45th Annual
Meeting of the American Society of Hematology (abstract 91).

Dr. Bennett explained that the study was an update of data
presented at the ASH conference 2 years ago. The concern was that patients with
low-grade NHL typically receive many cytotoxic regimens and local external-beam
radiotherapy over the 8- to 12-year course of their disease, and virtually all
of these agents are intrinsically carcinogenic. As a consequence, one of the
potential complications of therapy is MDS and AML. Indeed, the estimated
actuarial risk of tMDS/tAML associated with chemotherapy and radiotherapy at 8
years ranges from 4% to 17%.

Since 1990, more than 1,500 patients with low-grade NHL have
been treated with the Bexxar therapeutic regimen, which specifically targets
CD20 on normal and malignant lymphocytes and delivers both gamma and beta
radiation. Dr. Bennett noted that many durable long-term remissions have been
reported in patients treated with the Bexxar therapeutic regimen (see article
on page 13). "We investigated whether the systemic radiation from the Bexxar
therapeutic regimen increases the incidence of tMDS/tAML over that observed in
patients exposed to known leukemogenic agents," Dr. Bennett said.

The masked, independent review looked at 1,071 patients who
were enrolled in seven studies of Bexxar therapy. Of these, 995 patients had
relapsed/refractory low-grade NHL and had received a median of three prior
cytotoxic regimens, including alkylating agents, platinums, topoisomerase II
inhibitors, antimetabolites, and external-beam radiation therapy to greater
than one marrow-bearing region. The other 76 patients had follicular NHL and
received the Bexxar regimen as their initial therapy.

All patients had less than 25% bone marrow involvement. The
mCi dose of the Bexxar therapeutic regimen was adjusted to deliver 65 or 75 cGy
total body radiation dose depending on the patient’s pre-Bexxar platelet count
(100,000 to 150,000/mm3 or more than 150,000/mm3,
respectively).

Dr. Bennett reported that among 995 heavily pretreated
patients, there were 35 investigator-reported cases of tMDS/tAML, with a median
follow-up of 2 years. In contrast, among the 76 previously untreated patients,
there have been no reported cases of tMDS/tAML, with a median follow-up of 4.6
years.

Bone Marrow Sample Review

A single-reference hematomorpholo-gist reviewed the
available pre- and post-Bexxar bone marrow samples from the 35 tMDS/tAML
patients in a blinded fashion. After this review, the incidence of tMDS/tAML in
these Bexxar studies was reduced by 37%.

The reviewers found that two patients had no evidence of MDS
with stable pre- and post-Bexxar blood counts and one had asplastic anemia
before Bexxar therapy. Significantly, 9 patients were found to have tMDS in
their pre-Bexxar marrow (see Figure), and 1 patient had AML (erythroleukemia).

The annualized incidence of tMDS/tAML for previously treated
patients was 1.6% a year based on investigator assessments (35 cases), and 1.1%
a year based on the independent hematomorpholo-gist’s assessment (22 confirmed
cases).

Given the considerable variability in the incidence of tMDS/tAML in
low-grade NHL patients in the literature (an average of 10% in 10 years) and
the variety of statistical methods and diagnostic criteria used, Dr. Bennett
said that treatment decisions must be based on risk-to-benefit ratios that are
"reasonable and rational."

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